CN114762676A - 一种缓释制剂组合物 - Google Patents
一种缓释制剂组合物 Download PDFInfo
- Publication number
- CN114762676A CN114762676A CN202110051096.4A CN202110051096A CN114762676A CN 114762676 A CN114762676 A CN 114762676A CN 202110051096 A CN202110051096 A CN 202110051096A CN 114762676 A CN114762676 A CN 114762676A
- Authority
- CN
- China
- Prior art keywords
- acid
- oil
- pharmaceutical composition
- pharmaceutically acceptable
- glyceryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims description 149
- 239000003405 delayed action preparation Substances 0.000 title description 5
- 239000003381 stabilizer Substances 0.000 claims abstract description 42
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 40
- 239000004480 active ingredient Substances 0.000 claims abstract description 30
- 239000007788 liquid Substances 0.000 claims abstract description 27
- 230000000202 analgesic effect Effects 0.000 claims abstract description 16
- 238000013268 sustained release Methods 0.000 claims abstract description 9
- 239000012730 sustained-release form Substances 0.000 claims abstract description 9
- 239000003921 oil Substances 0.000 claims description 59
- 235000019198 oils Nutrition 0.000 claims description 59
- -1 sphingomyelin Chemical compound 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 24
- 238000009472 formulation Methods 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000003607 modifier Substances 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 14
- 239000011259 mixed solution Substances 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 11
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 claims description 11
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 11
- 125000001931 aliphatic group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 9
- 239000003589 local anesthetic agent Substances 0.000 claims description 9
- GFAZGHREJPXDMH-UHFFFAOYSA-N 1,3-dipalmitoylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCC GFAZGHREJPXDMH-UHFFFAOYSA-N 0.000 claims description 8
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 8
- CITHEXJVPOWHKC-UUWRZZSWSA-N 1,2-di-O-myristoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCC CITHEXJVPOWHKC-UUWRZZSWSA-N 0.000 claims description 7
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 7
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 239000004359 castor oil Substances 0.000 claims description 7
- 235000019438 castor oil Nutrition 0.000 claims description 7
- 235000012000 cholesterol Nutrition 0.000 claims description 7
- 229960003724 dimyristoylphosphatidylcholine Drugs 0.000 claims description 7
- 239000008344 egg yolk phospholipid Substances 0.000 claims description 7
- 229940068998 egg yolk phospholipid Drugs 0.000 claims description 7
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 7
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- IHNKQIMGVNPMTC-UHFFFAOYSA-N (2-hydroxy-3-octadecanoyloxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C IHNKQIMGVNPMTC-UHFFFAOYSA-N 0.000 claims description 6
- SLKDGVPOSSLUAI-PGUFJCEWSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine zwitterion Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCCCC SLKDGVPOSSLUAI-PGUFJCEWSA-N 0.000 claims description 6
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 6
- IJFVSSZAOYLHEE-SSEXGKCCSA-N 1,2-dilauroyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCC IJFVSSZAOYLHEE-SSEXGKCCSA-N 0.000 claims description 6
- YFWHNAWEOZTIPI-DIPNUNPCSA-N 1,2-dioctadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCCCC YFWHNAWEOZTIPI-DIPNUNPCSA-N 0.000 claims description 6
- LVNGJLRDBYCPGB-UHFFFAOYSA-N 1,2-distearoylphosphatidylethanolamine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP([O-])(=O)OCC[NH3+])OC(=O)CCCCCCCCCCCCCCCCC LVNGJLRDBYCPGB-UHFFFAOYSA-N 0.000 claims description 6
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 claims description 6
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 6
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 6
- NEZDNQCXEZDCBI-UHFFFAOYSA-N 2-azaniumylethyl 2,3-di(tetradecanoyloxy)propyl phosphate Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCCCCCCCC NEZDNQCXEZDCBI-UHFFFAOYSA-N 0.000 claims description 6
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 claims description 6
- KLFKZIQAIPDJCW-HTIIIDOHSA-N Dipalmitoylphosphatidylserine Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCC KLFKZIQAIPDJCW-HTIIIDOHSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- FVJZSBGHRPJMMA-IOLBBIBUSA-N PG(18:0/18:0) Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-IOLBBIBUSA-N 0.000 claims description 6
- DSNRWDQKZIEDDB-GCMPNPAFSA-N [(2r)-3-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-2-[(z)-octadec-9-enoyl]oxypropyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC DSNRWDQKZIEDDB-GCMPNPAFSA-N 0.000 claims description 6
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 229960005160 dimyristoylphosphatidylglycerol Drugs 0.000 claims description 6
- MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 claims description 6
- BPHQZTVXXXJVHI-AJQTZOPKSA-N ditetradecanoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-AJQTZOPKSA-N 0.000 claims description 6
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000787 lecithin Substances 0.000 claims description 6
- 229940067606 lecithin Drugs 0.000 claims description 6
- 235000010445 lecithin Nutrition 0.000 claims description 6
- 150000003905 phosphatidylinositols Chemical class 0.000 claims description 6
- 150000003904 phospholipids Chemical class 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 6
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 5
- PAZGBAOHGQRCBP-DDDNOICHSA-N 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C/CCCCCCCC PAZGBAOHGQRCBP-DDDNOICHSA-N 0.000 claims description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 5
- 229930003427 Vitamin E Natural products 0.000 claims description 5
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 5
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 239000004094 surface-active agent Substances 0.000 claims description 5
- 235000019165 vitamin E Nutrition 0.000 claims description 5
- 239000011709 vitamin E Substances 0.000 claims description 5
- 229940046009 vitamin E Drugs 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 230000000561 anti-psychotic effect Effects 0.000 claims description 4
- 239000001961 anticonvulsive agent Substances 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 4
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 claims description 4
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- QAIPRVGONGVQAS-DUXPYHPUSA-N trans-caffeic acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-DUXPYHPUSA-N 0.000 claims description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- DMBUODUULYCPAK-UHFFFAOYSA-N 1,3-bis(docosanoyloxy)propan-2-yl docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCCCCCC DMBUODUULYCPAK-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 239000005639 Lauric acid Substances 0.000 claims description 3
- 235000021314 Palmitic acid Nutrition 0.000 claims description 3
- QHZLMUACJMDIAE-UHFFFAOYSA-N Palmitic acid monoglyceride Natural products CCCCCCCCCCCCCCCC(=O)OCC(O)CO QHZLMUACJMDIAE-UHFFFAOYSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 229960003965 antiepileptics Drugs 0.000 claims description 3
- 229960002903 benzyl benzoate Drugs 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 229940074045 glyceryl distearate Drugs 0.000 claims description 3
- 229940046813 glyceryl palmitostearate Drugs 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000001384 succinic acid Substances 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 claims description 3
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 claims description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- ACEAELOMUCBPJP-UHFFFAOYSA-N (E)-3,4,5-trihydroxycinnamic acid Natural products OC(=O)C=CC1=CC(O)=C(O)C(O)=C1 ACEAELOMUCBPJP-UHFFFAOYSA-N 0.000 claims description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- AFSHUZFNMVJNKX-UHFFFAOYSA-N 1,2-di-(9Z-octadecenoyl)glycerol Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCC=CCCCCCCCC AFSHUZFNMVJNKX-UHFFFAOYSA-N 0.000 claims description 2
- AFSHUZFNMVJNKX-LLWMBOQKSA-N 1,2-dioleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](CO)OC(=O)CCCCCCC\C=C/CCCCCCCC AFSHUZFNMVJNKX-LLWMBOQKSA-N 0.000 claims description 2
- QHZLMUACJMDIAE-SFHVURJKSA-N 1-hexadecanoyl-sn-glycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)CO QHZLMUACJMDIAE-SFHVURJKSA-N 0.000 claims description 2
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 claims description 2
- SWNIFANHJGMBIM-UHFFFAOYSA-N 2,3-dihydroxypropyl hexadecanoate;octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCC(=O)OCC(O)CO SWNIFANHJGMBIM-UHFFFAOYSA-N 0.000 claims description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 2
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 2
- AWQSAIIDOMEEOD-UHFFFAOYSA-N 5,5-Dimethyl-4-(3-oxobutyl)dihydro-2(3H)-furanone Chemical compound CC(=O)CCC1CC(=O)OC1(C)C AWQSAIIDOMEEOD-UHFFFAOYSA-N 0.000 claims description 2
- AMEMLELAMQEAIA-UHFFFAOYSA-N 6-(tert-butyl)thieno[3,2-d]pyrimidin-4(3H)-one Chemical compound N1C=NC(=O)C2=C1C=C(C(C)(C)C)S2 AMEMLELAMQEAIA-UHFFFAOYSA-N 0.000 claims description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 2
- 235000019489 Almond oil Nutrition 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 240000002791 Brassica napus Species 0.000 claims description 2
- 235000004977 Brassica sinapistrum Nutrition 0.000 claims description 2
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 2
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 2
- 244000020551 Helianthus annuus Species 0.000 claims description 2
- 235000003222 Helianthus annuus Nutrition 0.000 claims description 2
- 239000005642 Oleic acid Substances 0.000 claims description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019483 Peanut oil Nutrition 0.000 claims description 2
- 239000005643 Pelargonic acid Substances 0.000 claims description 2
- 229930182555 Penicillin Natural products 0.000 claims description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 2
- 235000019485 Safflower oil Nutrition 0.000 claims description 2
- 235000019486 Sunflower oil Nutrition 0.000 claims description 2
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 2
- 239000008168 almond oil Substances 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 230000001773 anti-convulsant effect Effects 0.000 claims description 2
- 230000001430 anti-depressive effect Effects 0.000 claims description 2
- 230000003474 anti-emetic effect Effects 0.000 claims description 2
- 230000003409 anti-rejection Effects 0.000 claims description 2
- 230000002421 anti-septic effect Effects 0.000 claims description 2
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 2
- 239000000935 antidepressant agent Substances 0.000 claims description 2
- 229940005513 antidepressants Drugs 0.000 claims description 2
- 239000000729 antidote Substances 0.000 claims description 2
- 239000002111 antiemetic agent Substances 0.000 claims description 2
- 239000000939 antiparkinson agent Substances 0.000 claims description 2
- 229940043671 antithyroid preparations Drugs 0.000 claims description 2
- 239000002249 anxiolytic agent Substances 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000010480 babassu oil Substances 0.000 claims description 2
- 239000010473 blackcurrant seed oil Substances 0.000 claims description 2
- 235000021324 borage oil Nutrition 0.000 claims description 2
- 229940074360 caffeic acid Drugs 0.000 claims description 2
- 235000004883 caffeic acid Nutrition 0.000 claims description 2
- 239000010495 camellia oil Substances 0.000 claims description 2
- 239000000828 canola oil Substances 0.000 claims description 2
- 235000019519 canola oil Nutrition 0.000 claims description 2
- QAIPRVGONGVQAS-UHFFFAOYSA-N cis-caffeic acid Natural products OC(=O)C=CC1=CC=C(O)C(O)=C1 QAIPRVGONGVQAS-UHFFFAOYSA-N 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 235000005687 corn oil Nutrition 0.000 claims description 2
- 239000002285 corn oil Substances 0.000 claims description 2
- 235000012343 cottonseed oil Nutrition 0.000 claims description 2
- 239000002385 cottonseed oil Substances 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 235000021323 fish oil Nutrition 0.000 claims description 2
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 claims description 2
- 229940081618 glyceryl monobehenate Drugs 0.000 claims description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 2
- 239000008240 homogeneous mixture Substances 0.000 claims description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 2
- 229940033357 isopropyl laurate Drugs 0.000 claims description 2
- 229940074928 isopropyl myristate Drugs 0.000 claims description 2
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 claims description 2
- 229940075495 isopropyl palmitate Drugs 0.000 claims description 2
- 229940089456 isopropyl stearate Drugs 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940099690 malic acid Drugs 0.000 claims description 2
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 2
- 229960002446 octanoic acid Drugs 0.000 claims description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 2
- 239000004006 olive oil Substances 0.000 claims description 2
- 235000008390 olive oil Nutrition 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229940116315 oxalic acid Drugs 0.000 claims description 2
- 239000003346 palm kernel oil Substances 0.000 claims description 2
- 235000019865 palm kernel oil Nutrition 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000312 peanut oil Substances 0.000 claims description 2
- 229940049954 penicillin Drugs 0.000 claims description 2
- ZPWFUIUNWDIYCJ-UHFFFAOYSA-N propan-2-yl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(C)C ZPWFUIUNWDIYCJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 235000005713 safflower oil Nutrition 0.000 claims description 2
- 239000003813 safflower oil Substances 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 230000004799 sedative–hypnotic effect Effects 0.000 claims description 2
- 239000008159 sesame oil Substances 0.000 claims description 2
- 235000011803 sesame oil Nutrition 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 235000012424 soybean oil Nutrition 0.000 claims description 2
- 239000003549 soybean oil Substances 0.000 claims description 2
- 239000003270 steroid hormone Substances 0.000 claims description 2
- 239000002600 sunflower oil Substances 0.000 claims description 2
- 229960001367 tartaric acid Drugs 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 229960002622 triacetin Drugs 0.000 claims description 2
- 229940005605 valeric acid Drugs 0.000 claims description 2
- 238000004806 packaging method and process Methods 0.000 claims 2
- 208000030507 AIDS Diseases 0.000 claims 1
- 244000068988 Glycine max Species 0.000 claims 1
- 235000010469 Glycine max Nutrition 0.000 claims 1
- 208000018737 Parkinson disease Diseases 0.000 claims 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims 1
- 230000003288 anthiarrhythmic effect Effects 0.000 claims 1
- 230000003556 anti-epileptic effect Effects 0.000 claims 1
- 230000003276 anti-hypertensive effect Effects 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 claims 1
- 230000000118 anti-neoplastic effect Effects 0.000 claims 1
- 230000000648 anti-parkinson Effects 0.000 claims 1
- 230000003208 anti-thyroid effect Effects 0.000 claims 1
- 230000002365 anti-tubercular Effects 0.000 claims 1
- 230000000949 anxiolytic effect Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 208000002672 hepatitis B Diseases 0.000 claims 1
- 230000002218 hypoglycaemic effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 15
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 206010002091 Anaesthesia Diseases 0.000 abstract description 2
- 230000037005 anaesthesia Effects 0.000 abstract description 2
- 230000002459 sustained effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 24
- 229940079593 drug Drugs 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 19
- 229960003150 bupivacaine Drugs 0.000 description 18
- 230000014759 maintenance of location Effects 0.000 description 14
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 12
- 229960001929 meloxicam Drugs 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 11
- ZKMNUMMKYBVTFN-HNNXBMFYSA-N (S)-ropivacaine Chemical compound CCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C ZKMNUMMKYBVTFN-HNNXBMFYSA-N 0.000 description 10
- 229960001549 ropivacaine Drugs 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000008280 blood Substances 0.000 description 9
- 210000004369 blood Anatomy 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- 241000700159 Rattus Species 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- LEBVLXFERQHONN-INIZCTEOSA-N levobupivacaine Chemical compound CCCCN1CCCC[C@H]1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-INIZCTEOSA-N 0.000 description 7
- 229960004288 levobupivacaine Drugs 0.000 description 7
- 230000036470 plasma concentration Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000007711 solidification Methods 0.000 description 7
- 230000008023 solidification Effects 0.000 description 7
- 241000282472 Canis lupus familiaris Species 0.000 description 6
- 229960000590 celecoxib Drugs 0.000 description 6
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000002502 liposome Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 238000000518 rheometry Methods 0.000 description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- 208000000114 Pain Threshold Diseases 0.000 description 4
- 208000004550 Postoperative Pain Diseases 0.000 description 4
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 4
- 229940052294 amide local anesthetics Drugs 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 125000005456 glyceride group Chemical group 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000037040 pain threshold Effects 0.000 description 4
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000010254 subcutaneous injection Methods 0.000 description 4
- 239000007929 subcutaneous injection Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960002117 triamcinolone acetonide Drugs 0.000 description 4
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 4
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- JLPULHDHAOZNQI-JLOPVYAASA-N [(2r)-3-hexadecanoyloxy-2-[(9e,12e)-octadeca-9,12-dienoyl]oxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC JLPULHDHAOZNQI-JLOPVYAASA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- QLBHNVFOQLIYTH-UHFFFAOYSA-L dipotassium;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [K+].[K+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O QLBHNVFOQLIYTH-UHFFFAOYSA-L 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 229940049654 glyceryl behenate Drugs 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229960004752 ketorolac Drugs 0.000 description 3
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 3
- 229960004194 lidocaine Drugs 0.000 description 3
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 description 3
- 229960002409 mepivacaine Drugs 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 2
- 229930182837 (R)-adrenaline Natural products 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 2
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 2
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 2
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 2
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 208000004454 Hyperalgesia Diseases 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 238000001467 acupuncture Methods 0.000 description 2
- 239000000048 adrenergic agonist Substances 0.000 description 2
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 2
- VIROVYVQCGLCII-UHFFFAOYSA-N amobarbital Chemical compound CC(C)CCC1(CC)C(=O)NC(=O)NC1=O VIROVYVQCGLCII-UHFFFAOYSA-N 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 229960002274 atenolol Drugs 0.000 description 2
- 229940092705 beclomethasone Drugs 0.000 description 2
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 2
- 229960004277 benorilate Drugs 0.000 description 2
- FEJKLNWAOXSSNR-UHFFFAOYSA-N benorilate Chemical compound C1=CC(NC(=O)C)=CC=C1OC(=O)C1=CC=CC=C1OC(C)=O FEJKLNWAOXSSNR-UHFFFAOYSA-N 0.000 description 2
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 2
- 229960001950 benzethonium chloride Drugs 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- 229960002537 betamethasone Drugs 0.000 description 2
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 2
- 229960000962 bufexamac Drugs 0.000 description 2
- MXJWRABVEGLYDG-UHFFFAOYSA-N bufexamac Chemical compound CCCCOC1=CC=C(CC(=O)NO)C=C1 MXJWRABVEGLYDG-UHFFFAOYSA-N 0.000 description 2
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 description 2
- 229960002842 clobetasol Drugs 0.000 description 2
- FCSHDIVRCWTZOX-DVTGEIKXSA-N clobetasol Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O FCSHDIVRCWTZOX-DVTGEIKXSA-N 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 229960004544 cortisone Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- 229960004253 dexmedetomidine Drugs 0.000 description 2
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 description 2
- 229960003529 diazepam Drugs 0.000 description 2
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 2
- 229960004515 diclofenac potassium Drugs 0.000 description 2
- KXZOIWWTXOCYKR-UHFFFAOYSA-M diclofenac potassium Chemical compound [K+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KXZOIWWTXOCYKR-UHFFFAOYSA-M 0.000 description 2
- 229960001193 diclofenac sodium Drugs 0.000 description 2
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 229960005139 epinephrine Drugs 0.000 description 2
- 229960005293 etodolac Drugs 0.000 description 2
- XFBVBWWRPKNWHW-UHFFFAOYSA-N etodolac Chemical compound C1COC(CC)(CC(O)=O)C2=N[C]3C(CC)=CC=CC3=C21 XFBVBWWRPKNWHW-UHFFFAOYSA-N 0.000 description 2
- 229960001419 fenoprofen Drugs 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 229960002390 flurbiprofen Drugs 0.000 description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 2
- 229960004580 glibenclamide Drugs 0.000 description 2
- 239000003862 glucocorticoid Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 2
- 229940074047 glyceryl cocoate Drugs 0.000 description 2
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 229940116364 hard fat Drugs 0.000 description 2
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 2
- 229960002202 lornoxicam Drugs 0.000 description 2
- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 description 2
- 229960002373 loxoprofen Drugs 0.000 description 2
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229960004584 methylprednisolone Drugs 0.000 description 2
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 2
- 229960002237 metoprolol Drugs 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 229960004270 nabumetone Drugs 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- 229960000965 nimesulide Drugs 0.000 description 2
- HYWYRSMBCFDLJT-UHFFFAOYSA-N nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 229960004662 parecoxib Drugs 0.000 description 2
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 2
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229960002895 phenylbutazone Drugs 0.000 description 2
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 2
- 229960002702 piroxicam Drugs 0.000 description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229960005205 prednisolone Drugs 0.000 description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229960003712 propranolol Drugs 0.000 description 2
- 229960000371 rofecoxib Drugs 0.000 description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 2
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 2
- 239000008347 soybean phospholipid Substances 0.000 description 2
- 229960001203 stavudine Drugs 0.000 description 2
- 239000001797 sucrose acetate isobutyrate Substances 0.000 description 2
- UVGUPMLLGBCFEJ-SWTLDUCYSA-N sucrose acetate isobutyrate Chemical compound CC(C)C(=O)O[C@H]1[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O[C@@]1(COC(C)=O)O[C@@H]1[C@H](OC(=O)C(C)C)[C@@H](OC(=O)C(C)C)[C@H](OC(=O)C(C)C)[C@@H](COC(C)=O)O1 UVGUPMLLGBCFEJ-SWTLDUCYSA-N 0.000 description 2
- 235000010983 sucrose acetate isobutyrate Nutrition 0.000 description 2
- 229960000894 sulindac Drugs 0.000 description 2
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 2
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 description 2
- 229960000488 tizanidine Drugs 0.000 description 2
- 229960004380 tramadol Drugs 0.000 description 2
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 2
- 229960002004 valdecoxib Drugs 0.000 description 2
- IGLYMJRIWWIQQE-QUOODJBBSA-N (1S,2R)-2-phenylcyclopropan-1-amine (1R,2S)-2-phenylcyclopropan-1-amine Chemical compound N[C@H]1C[C@@H]1C1=CC=CC=C1.N[C@@H]1C[C@H]1C1=CC=CC=C1 IGLYMJRIWWIQQE-QUOODJBBSA-N 0.000 description 1
- VUMQHLSPUAFKKK-HIFRSBDPSA-N (1r,2r)-1-(3-methoxyphenyl)-2-(methylaminomethyl)cyclohexan-1-ol Chemical compound CNC[C@H]1CCCC[C@]1(O)C1=CC=CC(OC)=C1 VUMQHLSPUAFKKK-HIFRSBDPSA-N 0.000 description 1
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- HGPQAWTZLJXCTC-SSTWWWIQSA-N (4r,4ar,7s,7ar,12bs)-7,9-dimethoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline Chemical compound C([C@@H](N(CC1)C)[C@@H]2C=C[C@@H]3OC)C4=CC=C(OC)C5=C4[C@@]21[C@H]3O5 HGPQAWTZLJXCTC-SSTWWWIQSA-N 0.000 description 1
- XFDJYSQDBULQSI-QFIPXVFZSA-N (R)-doxapram Chemical compound C([C@H]1CN(C(C1(C=1C=CC=CC=1)C=1C=CC=CC=1)=O)CC)CN1CCOCC1 XFDJYSQDBULQSI-QFIPXVFZSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- WSPOMRSOLSGNFJ-AUWJEWJLSA-N (Z)-chlorprothixene Chemical compound C1=C(Cl)C=C2C(=C/CCN(C)C)\C3=CC=CC=C3SC2=C1 WSPOMRSOLSGNFJ-AUWJEWJLSA-N 0.000 description 1
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000006018 1-methyl-ethenyl group Chemical group 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 229940114069 12-hydroxystearate Drugs 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 description 1
- 125000006020 2-methyl-1-propenyl group Chemical group 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 description 1
- AURFZBICLPNKBZ-FZCSVUEKSA-N 3beta-hydroxy-5alpha-pregnan-20-one Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 AURFZBICLPNKBZ-FZCSVUEKSA-N 0.000 description 1
- IJWPAFMIFNSIGD-UHFFFAOYSA-N 4-[3-(3-fluorophenyl)-5,5-dimethyl-4-oxofuran-2-yl]benzenesulfonamide Chemical compound O=C1C(C)(C)OC(C=2C=CC(=CC=2)S(N)(=O)=O)=C1C1=CC=CC(F)=C1 IJWPAFMIFNSIGD-UHFFFAOYSA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- 101800005049 Beta-endorphin Proteins 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 229940124638 COX inhibitor Drugs 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 108010065372 Dynorphins Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 108010092674 Enkephalins Proteins 0.000 description 1
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
- 108010011459 Exenatide Proteins 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 1
- PGTVWKLGGCQMBR-FLBATMFCSA-N Ganaxolone Chemical compound C([C@@H]1CC2)[C@](C)(O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 PGTVWKLGGCQMBR-FLBATMFCSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 208000029836 Inguinal Hernia Diseases 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- GGLZPLKKBSSKCX-YFKPBYRVSA-N L-ethionine Chemical compound CCSCC[C@H](N)C(O)=O GGLZPLKKBSSKCX-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 1
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 1
- 108010019598 Liraglutide Proteins 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- UILOTUUZKGTYFQ-UHFFFAOYSA-N Mafenide acetate Chemical compound CC(O)=O.NCC1=CC=C(S(N)(=O)=O)C=C1 UILOTUUZKGTYFQ-UHFFFAOYSA-N 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- GMZVRMREEHBGGF-UHFFFAOYSA-N Piracetam Chemical compound NC(=O)CN1CCCC1=O GMZVRMREEHBGGF-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- AURFZBICLPNKBZ-UHFFFAOYSA-N Pregnanolone Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(=O)C)C1(C)CC2 AURFZBICLPNKBZ-UHFFFAOYSA-N 0.000 description 1
- 102100027467 Pro-opiomelanocortin Human genes 0.000 description 1
- 102100024622 Proenkephalin-B Human genes 0.000 description 1
- KNAHARQHSZJURB-UHFFFAOYSA-N Propylthiouracile Chemical compound CCCC1=CC(=O)NC(=S)N1 KNAHARQHSZJURB-UHFFFAOYSA-N 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- VRDIULHPQTYCLN-UHFFFAOYSA-N Prothionamide Chemical compound CCCC1=CC(C(N)=S)=CC=N1 VRDIULHPQTYCLN-UHFFFAOYSA-N 0.000 description 1
- 101000835619 Rattus norvegicus Tubulin-specific chaperone A Proteins 0.000 description 1
- ZTVQQQVZCWLTDF-UHFFFAOYSA-N Remifentanil Chemical compound C1CN(CCC(=O)OC)CCC1(C(=O)OC)N(C(=O)CC)C1=CC=CC=C1 ZTVQQQVZCWLTDF-UHFFFAOYSA-N 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000002847 Surgical Wound Diseases 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229960004538 alprazolam Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 229960001301 amobarbital Drugs 0.000 description 1
- 229960002519 amoxapine Drugs 0.000 description 1
- QWGDMFLQWFTERH-UHFFFAOYSA-N amoxapine Chemical compound C12=CC(Cl)=CC=C2OC2=CC=CC=C2N=C1N1CCNCC1 QWGDMFLQWFTERH-UHFFFAOYSA-N 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- ZXNRTKGTQJPIJK-UHFFFAOYSA-N aniracetam Chemical compound C1=CC(OC)=CC=C1C(=O)N1C(=O)CCC1 ZXNRTKGTQJPIJK-UHFFFAOYSA-N 0.000 description 1
- 229960000793 aniracetam Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003200 antithyroid agent Substances 0.000 description 1
- 229940124976 antitubercular drug Drugs 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 229940116226 behenic acid Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 229960005274 benzocaine Drugs 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 229960002890 beraprost Drugs 0.000 description 1
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- WOPZMFQRCBYPJU-NTXHZHDSSA-N beta-endorphin Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)[C@@H](C)O)C1=CC=CC=C1 WOPZMFQRCBYPJU-NTXHZHDSSA-N 0.000 description 1
- VHYCDWMUTMEGQY-UHFFFAOYSA-N bisoprolol Chemical compound CC(C)NCC(O)COC1=CC=C(COCCOC(C)C)C=C1 VHYCDWMUTMEGQY-UHFFFAOYSA-N 0.000 description 1
- 229960002781 bisoprolol Drugs 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229960001050 bupivacaine hydrochloride Drugs 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 229960004205 carbidopa Drugs 0.000 description 1
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- UKTAZPQNNNJVKR-KJGYPYNMSA-N chembl2368925 Chemical compound C1=CC=C2C(C(O[C@@H]3C[C@@H]4C[C@H]5C[C@@H](N4CC5=O)C3)=O)=CNC2=C1 UKTAZPQNNNJVKR-KJGYPYNMSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 229960001552 chlorprothixene Drugs 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 1
- 229960003120 clonazepam Drugs 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229960005107 darunavir Drugs 0.000 description 1
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- NGPTYCZGBCGWBE-UHFFFAOYSA-N decanoic acid hexadecanoic acid octadecanoic acid octanoic acid propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O NGPTYCZGBCGWBE-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003461 dezocine Drugs 0.000 description 1
- VTMVHDZWSFQSQP-VBNZEHGJSA-N dezocine Chemical compound C1CCCC[C@H]2CC3=CC=C(O)C=C3[C@]1(C)[C@H]2N VTMVHDZWSFQSQP-VBNZEHGJSA-N 0.000 description 1
- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 description 1
- 229960000920 dihydrocodeine Drugs 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960003413 dolasetron Drugs 0.000 description 1
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 description 1
- 229960001253 domperidone Drugs 0.000 description 1
- 229960002955 doxapram Drugs 0.000 description 1
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- BZEWSEKUUPWQDQ-UHFFFAOYSA-N dyclonine Chemical compound C1=CC(OCCCC)=CC=C1C(=O)CCN1CCCCC1 BZEWSEKUUPWQDQ-UHFFFAOYSA-N 0.000 description 1
- 229960000385 dyclonine Drugs 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 229960000366 emtricitabine Drugs 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960000980 entecavir Drugs 0.000 description 1
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 description 1
- 229960001123 epoprostenol Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 description 1
- 229960002049 etravirine Drugs 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 229960001519 exenatide Drugs 0.000 description 1
- 229940042577 exparel Drugs 0.000 description 1
- 229960002428 fentanyl Drugs 0.000 description 1
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- OFBIFZUFASYYRE-UHFFFAOYSA-N flumazenil Chemical compound C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 description 1
- 229960004381 flumazenil Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 229950006567 ganaxolone Drugs 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229960000346 gliclazide Drugs 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960001381 glipizide Drugs 0.000 description 1
- 235000003969 glutathione Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 229940074046 glyceryl laurate Drugs 0.000 description 1
- 229940074050 glyceryl myristate Drugs 0.000 description 1
- 229940096898 glyceryl palmitate Drugs 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 229940015042 glycopyrrolate Drugs 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 229960003727 granisetron Drugs 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 1
- 229960000240 hydrocodone Drugs 0.000 description 1
- 229940099578 hydrogenated soybean lecithin Drugs 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 229960002240 iloprost Drugs 0.000 description 1
- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- OWFXIOWLTKNBAP-UHFFFAOYSA-N isoamyl nitrite Chemical compound CC(C)CCON=O OWFXIOWLTKNBAP-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
- 229960003827 isosorbide mononitrate Drugs 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 229960002701 liraglutide Drugs 0.000 description 1
- VOBHXZCDAVEXEY-JSGCOSHPSA-N lisdexamfetamine Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)CC1=CC=CC=C1 VOBHXZCDAVEXEY-JSGCOSHPSA-N 0.000 description 1
- 229960001451 lisdexamfetamine Drugs 0.000 description 1
- 229960005209 lofexidine Drugs 0.000 description 1
- KSMAGQUYOIHWFS-UHFFFAOYSA-N lofexidine Chemical compound N=1CCNC=1C(C)OC1=C(Cl)C=CC=C1Cl KSMAGQUYOIHWFS-UHFFFAOYSA-N 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229960002721 mafenide acetate Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- PMRYVIKBURPHAH-UHFFFAOYSA-N methimazole Chemical compound CN1C=CNC1=S PMRYVIKBURPHAH-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- NETZHAKZCGBWSS-CEDHKZHLSA-N nalbuphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@@H]3O)CN2CC1CCC1 NETZHAKZCGBWSS-CEDHKZHLSA-N 0.000 description 1
- 229960000805 nalbuphine Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- IAIWVQXQOWNYOU-FPYGCLRLSA-N nitrofural Chemical compound NC(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 IAIWVQXQOWNYOU-FPYGCLRLSA-N 0.000 description 1
- 229960000349 nitrofural Drugs 0.000 description 1
- UEHLXXJAWYWUGI-UHFFFAOYSA-M nitromersol Chemical compound CC1=CC=C([N+]([O-])=O)C2=C1O[Hg]2 UEHLXXJAWYWUGI-UHFFFAOYSA-M 0.000 description 1
- 229940118238 nitromersol Drugs 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229960001158 nortriptyline Drugs 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 229960004535 oxazepam Drugs 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- 229960001227 oxiracetam Drugs 0.000 description 1
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- 229960001057 paliperidone Drugs 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 229960002131 palonosetron Drugs 0.000 description 1
- CPZBLNMUGSZIPR-NVXWUHKLSA-N palonosetron Chemical compound C1N(CC2)CCC2[C@@H]1N1C(=O)C(C=CC=C2CCC3)=C2[C@H]3C1 CPZBLNMUGSZIPR-NVXWUHKLSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000008063 pharmaceutical solvent Substances 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 229960000964 phenelzine Drugs 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 description 1
- 229960001999 phentolamine Drugs 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229960004526 piracetam Drugs 0.000 description 1
- 229950006009 polmacoxib Drugs 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 1
- 229960000244 procainamide Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 229960002662 propylthiouracil Drugs 0.000 description 1
- 229960000918 protionamide Drugs 0.000 description 1
- 239000003196 psychodysleptic agent Substances 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 1
- DCBSHORRWZKAKO-UHFFFAOYSA-N rac-1-monomyristoylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(O)CO DCBSHORRWZKAKO-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229960003394 remifentanil Drugs 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- KQPKPCNLIDLUMF-UHFFFAOYSA-N secobarbital Chemical compound CCCC(C)C1(CC=C)C(=O)NC(=O)NC1=O KQPKPCNLIDLUMF-UHFFFAOYSA-N 0.000 description 1
- 229960002060 secobarbital Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical compound C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- 229960004739 sufentanil Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- KWTWDQCKEHXFFR-SMDDNHRTSA-N tapentadol Chemical compound CN(C)C[C@H](C)[C@@H](CC)C1=CC=CC(O)=C1 KWTWDQCKEHXFFR-SMDDNHRTSA-N 0.000 description 1
- 229960005126 tapentadol Drugs 0.000 description 1
- 229960005311 telbivudine Drugs 0.000 description 1
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- JCQBWMAWTUBARI-UHFFFAOYSA-N tert-butyl 3-ethenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(C=C)C1 JCQBWMAWTUBARI-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HPFVBGJFAYZEBE-ZLQWOROUSA-N testosterone cypionate Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(CCC(=O)C=C4CC3)C)CC[C@@]21C)C(=O)CCC1CCCC1 HPFVBGJFAYZEBE-ZLQWOROUSA-N 0.000 description 1
- 229960000921 testosterone cypionate Drugs 0.000 description 1
- VOCBWIIFXDYGNZ-IXKNJLPQSA-N testosterone enanthate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCC)[C@@]1(C)CC2 VOCBWIIFXDYGNZ-IXKNJLPQSA-N 0.000 description 1
- UDSFVOAUHKGBEK-CNQKSJKFSA-N testosterone undecanoate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCCCCCCCC)[C@@]1(C)CC2 UDSFVOAUHKGBEK-CNQKSJKFSA-N 0.000 description 1
- 229960000746 testosterone undecanoate Drugs 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 229960002372 tetracaine Drugs 0.000 description 1
- 229960002178 thiamazole Drugs 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 229960005032 treprostinil Drugs 0.000 description 1
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- ZNRGQMMCGHDTEI-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CNC2=C1 ZNRGQMMCGHDTEI-ITGUQSILSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Anesthesiology (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及一种药物组合物,包含液体油,药学上可接受的凝胶因子,药学上可接受的稳定剂和药学上的活性成分。所述药物组合物尤其适用于具有麻醉、镇痛活性的药物制剂开发,相对于其他缓释镇痛药体系具有更多的优势,例如对于镇痛活性成分的释放持续稳定,不仅可以注射给药,而且适用于稳定便捷的局部给药,患者耐受性好,副作用少。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种缓释制剂组合物及其制备方法和用途。
背景技术
手术后疼痛是手术后即刻发生的急性疼痛,通常持续不超过3~7天,如果不能在初始状态下被充分控制,则可能发展为慢性疼痛。目前常用的临床治疗手段是采用镇痛泵进行治疗,但是镇痛泵里含有的药物多为阿片类镇痛药和一些辅助镇痛药如曲马多等,尽管疗效较好,但也伴随着一系列副作用如呼吸抑制、恶心呕吐、低血压及潜在成瘾性等。
采用局麻药治疗术后疼痛可以避免上述不良反应,但是局麻药通常作用时间较短,单次给药后药效仅维持数小时,无法满足术后疼痛的治疗周期。因此开发长效局麻药制剂是目前的研究热点。
目前上市的长效局麻药制剂有PACIRA开发的布比卡因多囊脂质体混悬注射液,商品名为用于治疗术后疼痛及神经阻滞,镇痛效果可持续24小时。将布比卡因包裹在多囊脂质体中能起到良好的缓释作用,但是多囊脂质体制备工艺复杂,且对储藏条件要求高。
2020年8月28日,FDA批准Innocoll公司盐酸布比卡因植入剂,用于成人腹股沟疝修补术,在给药部位可持续24小时镇痛。但由于海绵体积较大,可能导致切口部位肿胀,此外由于所需手术创面较大,后期适应症拓展空间较小。
Heron Therapeutics Inc开发的(HTX-011)复方布比卡因美洛昔康溶液已于2020年9月24日被EMA批准,成为全球第三个长效布比卡因制剂。Zynrelef采用高分子材料聚原酸酯作为缓释载体,可能存在给药部位降解过慢的风险。
此外,DURECT公司开发了一种以小分子酯作为缓释载体的长效布比卡因制剂相关专利CN101035562公开了一种含有布比卡因、蔗糖醋酸异丁酸酯(SAIB)和苯甲醇的药物组合物。目前已进入III期临床,但临床结果与布比卡因溶液相比未表现出统计学差异。Gilbert J.Grant博士开发了布比卡因的大多室脂质体(LMVV),与Exparel脂质体结构相同,但粒径、制备工艺和稳定性有差异,4℃储存有泄漏风险,目前进入临床I期。合肥合源药业有限公司开发了帕莫酸布比卡因共晶HYR-PB21-LA,由于溶解度仅为0.076mg/mL,在注射部位可实现长效释放。但存在制备工艺较为复杂等缺点。
专利CN111655236A公开了一种控释药物组合物,其包含生物相容性和可生物蚀解的半固体凝胶,所述半固体凝胶包含蓖麻油、胶凝剂、布比卡因和任选的皮质类固醇、镇痛剂或抗炎剂。其中蓖麻油和甘油酯的比例为10:1至6:3(w/w)。由于蓖麻油中含有不饱和脂肪链,在储存过程中可能存在被氧化的风险,此外由于蓖麻油比例较高,随着放置时间的延长,可能存在析油风险。
因此,亟需开发一种适于药用,稳定性、安全性、耐受性和/或缓释性能得到改善的缓释制剂系统。
发明内容
为改善现有技术中存在的问题,本发明提供一种药物组合物,包括如下组分:
a.液体油
b.药学上可接受的凝胶因子,所述凝胶因子选自如式I的脂肪酸甘油酯中的一种或多种:
其中,R’、R”可以相同或不同,彼此独立地选自H或RaCO,R”’选自RaCO;每个Ra彼此独立地选自饱和或不饱和脂肪烃基;
c.药学上可接受的稳定剂,所述稳定剂选自式II或式III化合物中的一种或多种:
d.至少一种药学上的活性成分。
根据本发明的实施方案,所述式I中,每个Ra独立地选自烷基,优选的,每个Ra独立地选自C1-40烷基,更优选的,每个Ra独立地选自C7-40烷基;
在一些实施方案中,R’、R”选自H,R”’选自(C11-40烷基)C(=O);在一些实施方案中,R’选自H,R”选自RaCO,且R”、R”’中各自独立所选Ra烷基的碳数总和大于18;在一些实施方案中,R’、R”、R”’均选自RaCO,且R’、R”、R”’中各自独立所选Ra烷基的碳数总和大于17。
根据本发明的实施方案,所述b组分药学上可接受的凝胶因子包括月桂酸甘油酯、棕榈酸甘油酯、肉豆蔻酸甘油酯、硬脂酸甘油酯、C8-C18的混合脂肪酸甘油酯、山嵛酸甘油酯、棕榈酸硬脂酸甘油酯、椰油酸甘油酯、氢化椰子油甘油酯、氢化棕榈油甘油酯中的一种或多种;
优选的,所述b组分药学上可接受的凝胶因子包括例如单硬脂酸甘油酯,双硬脂酸甘油酯、三硬脂酸甘油酯、单山嵛酸甘油酯、双山嵛酸甘油酯、单棕榈酸硬脂酸甘油酯、双棕榈酸硬脂酸甘油酯、单棕榈酸甘油酯、双棕榈酸甘油酯、棕榈酸硬脂酸甘油酯中的一种或多种。
根据本发明的实施方案,所述式II中,每个R1、R2相同或不同,彼此独立地选自C10-30饱和或不饱和脂肪烃基,例如C13-21烷基;每个R3、R4、R5相同或不同,彼此独立地选自H或C1-10烷基,例如彼此独立地选自H,甲基,乙基;所述L选自C1-10亚烷基,优选的,L选自C1-6亚烷基,例如为亚甲基,亚乙基;
根据本发明的实施方案,式III所示化合物中,R选自C1-10烷基,例如C8-10烷基。
根据本发明的实施方案,所述c组分药学上可接受的稳定剂选自HSPC(氢化大豆磷脂)、DMPC(二肉豆蔻酰基磷脂酰胆碱)、DPPC(二棕榈酰基磷脂酰胆碱)、DSPC(二硬脂酰基磷脂酰胆碱)、DLPC(二月桂酰磷脂酰胆碱)、SPC大豆磷脂酰胆碱(大豆磷脂),EPC(蛋黄磷脂),油菜籽磷脂,向日葵磷脂,DEPC(二芥酰基卵磷脂),DOPC(二油酸酰基卵磷脂),POPC(棕榈酰基油酰基卵磷脂)、鞘磷脂、二硬脂酰磷脂酸(DSPA)、二油酰磷脂酰乙醇胺(DOPE)、二棕榈酰磷脂酸(DPPA)、肉豆蔻酰溶血磷脂(M-lysoPC)、棕榈酰溶血磷脂(P-lysoPC)、1-硬脂酰-溶血磷脂酰胆碱(S-lysoPC)、二棕榈酰磷脂酰乙醇胺(DPPE)、二硬脂酰磷脂酰乙醇胺(DSPE)、二油酰磷脂酰甘油(DOPG)、二肉豆蔻酰磷脂酰乙醇胺(DMPE)、二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰甘油(DPPG)、1-棕榈酰-2-油酰磷脂酰甘油(POPG)、二硬脂酰酰磷脂酰甘油(DSPG)、二棕榈酰磷酯酰丝氨酸(DPPS)、磷脂酰肌醇(PI)、胆固醇(CHO)中的一种或多种。
根据本发明的实施方案,所述药物组合物还包含e.至少一种药学上可接受的溶剂。
根据本发明的实施方案,所述药物组合物可以进一步包含g.药学上可接受的释放调节剂。
根据本发明的实施方案,所述药物组合物可以进一步包含f.药学上可接受的酸。
根据本发明的实施方案,所述液体油选自蓖麻油、芝麻油、玉米油、大豆油、橄榄油、红花油、棉籽油、花生油、鱼油、茶油、杏仁油、巴巴苏油、黑醋栗种子油、琉璃苣油、卡诺拉油、棕榈油、棕榈仁油、向日葵油、中链甘油三酯、二油酸甘油酯、单油酸甘油酯中的一种或多种组合。
根据本发明的实施方案,所述至少一种药学活性成分不限于治疗类型,并可为抗炎药、局麻药、镇痛药、抗精神失常药、抗焦虑药、镇静催眠药、抗抑郁药、抗高血压药、类固醇激素、抗癫痫药、杀菌剂、抗惊厥药、抗帕金森病药、中枢神经兴奋药、抗精神病药、抗心律失常药、抗心绞痛药、抗甲状腺药、解毒药、止吐药、降糖药、抗结核病药、抗艾滋病药、抗乙肝药、抗肿瘤药、抗排斥药及其混合物。
根据本发明的实施方案,合适的药学活性成分可选自下述化合物中的一种或多种的组合:阿司匹林,对乙酰氨基酚,贝诺酯,吲哚美辛,舒林酸,双氯芬酸,双氯芬酸钾,双氯芬酸钠,布洛芬,萘普生,氟比洛芬,氟比洛芬酯、洛索洛芬,萘丁美酮,酮咯酸,保泰松,丁苯羟酸,非诺洛芬,塞来昔布,罗非昔布,Polmacoxib,尼美舒利,美洛昔康,氯诺昔康,吡罗昔康,依托度酸,伐地考昔,帕瑞昔布,艾瑞昔布,卢米昔布。布比卡因,左旋布比卡因,罗哌卡因,甲哌卡因,利多卡因,普鲁卡因,苯佐卡因,丁卡因,达克罗宁。脑啡肽,强啡肽,β-内啡肽,纳曲酮,丁丙诺啡,吗啡,二甲基吗啡,可待因,双氢可待因,羟考酮、氢可酮、纳布啡,芬太尼,舒芬太尼,瑞芬太尼,曲马多,去甲曲马多,他喷他多,地佐辛,喷他佐辛,美沙酮,哌替啶,氯胺酮,地西泮,氯甲西泮,赖右苯丙胺,右丙氧芬,Difelikefalin,Oliceridine。氯丙嗪,三氟丙嗪,美索哒嗪,哌西他嗪,硫利达嗪,氯普噻吨。地西泮,阿普唑仑,氯硝西泮,奥沙西泮,丙咪嗪,阿密曲替林,多虑平,去甲替林,阿莫沙平,反苯环丙胺,苯乙肼。普鲁卡因胺,亚硝酸异戊酯,硝酸甘油,心得安,美托洛尔,哌唑嗪,酚妥拉明,咪噻吩,卡托普利,依那普利。可乐定,右美托咪定,肾上腺素,去甲肾上腺素,替扎尼定,α-甲基多巴,格隆溴铵。可的松,氢化可的松,倍他米松,曲安奈德,地塞米松,地塞米松酯,泼尼松,泼尼松龙,甲泼尼龙,倍氯米松,氯倍他索,黄体酮,睾酮,庚酸睾酮,十一烷酸睾酮,环戊丙酸睾酮,孕酮,氟维司群,别孕烯醇酮,Ganaxolone,苯妥英,乙妥英。苯扎氯铵,苄索氯铵,醋酸磺胺米隆,甲苄索氯铵,呋喃西林,硝甲酚汞。苯巴比妥、异戊巴比妥、戊巴比妥、司可巴比妥。卡比多巴,左旋多巴,阿尼西坦,奥拉西坦,吡拉西坦,多沙普仑,阿立哌唑,奥氮平,氟哌啶醇,喹硫平,利培酮,氯氮平,帕利哌酮,阿替洛尔,比索洛尔,美托洛尔。阿替洛尔,氨氯地平,尼莫地平,单硝酸异山梨酸酯,依前列醇,曲前列尼尔,伊洛前列素,贝前列素。甲巯咪唑,丙巯氧嘧啶,普萘洛尔,纳洛酮,洛非西定,氟马西尼,苯丙胺。格拉司琼,昂丹司琼,托烷司琼,多拉司琼,帕洛诺司琼,东莨菪碱,多潘立酮,格列吡嗪,格列本脲,格列美脲,优降糖,格列齐特,甲苯磺丁脲,利拉鲁肽,艾塞拉肽,度拉鲁肽,索马鲁肽。达芦那韦,多替拉韦钠,恩曲他滨,拉替拉韦,利托那韦,司他夫定,奈韦拉平,齐多夫定,司他夫定,依曲韦林,阿德福韦酯,恩替卡韦,替比夫定,拉米夫定,替诺福韦二吡呋酯,磷丙替诺福韦,氨硫脲,吡嗪酰胺,丙硫异烟胺,环磷酰胺,5-氟尿嘧啶,卡莫司汀,洛莫司汀,马法兰,苯丁酸氮芥,甲氨蝶呤,长春新碱,博来霉素,阿霉素,他莫昔芬,环孢素,他克莫司,依维莫司,西罗莫司以及所述化合物的药学可接受的盐,立体异构体,衍生物。
根据本发明的实施方案,所述药学活性成分选自酰胺类局麻药,例如选自布比卡因、罗哌卡因、左旋布比卡因、甲哌卡因、利多卡因及其盐。所述酰胺类局麻药的盐可以选自其脂肪酸盐和水溶性盐,形成盐的酸包括月桂酸、肉豆蔻酸、硬脂酸、棕榈酸、山嵛酸、花生酸、盐酸、磺酸、磷酸、醋酸、枸橼酸、马来酸、甲磺酸、富马酸、琥珀酸、乳酸等。
根据本发明的实施方案,所述药学活性成分除了包含酰胺类局麻药,还进一步包含第二种活性成分,所述药学活性成分可选自COX受体抑制药、肾上腺素受体激动药和糖皮质激素类药中的一种。所述COX受体抑制药包括非选择性COX抑制药和选择性COX-2抑制药。这些类别中代表的非甾体抗炎药包括,但不限于,下列非选择性COX抑制药:阿司匹林,对乙酰氨基酚,贝诺酯,吲哚美辛,舒林酸,双氯芬酸,双氯芬酸钾,双氯芬酸钠,布洛芬,萘普生,氟比洛芬,洛索洛芬,萘丁美酮,吡罗昔康,酮咯酸,保泰松,丁苯羟酸,非诺洛芬;下列选择性COX-2抑制药:塞来昔布,罗非昔布,尼美舒利,美洛昔康,氯诺昔康,依托度酸,伐地考昔,帕瑞昔布,艾瑞昔布,卢米昔布。以及所述化合物的药学可接受的盐,立体异构体,衍生物。所述的肾上腺素受体激动药主要是α2-肾上腺素受体激动药,包括但不限于可乐定,右美托咪定,肾上腺素,去甲肾上腺素,替扎尼定,α-甲基多巴。所述的糖皮质激素类药包括,但不限于可的松,氢化可的松,倍他米松,曲安奈德,地塞米松,泼尼松,泼尼松龙,甲泼尼龙,倍氯米松,氯倍他索。
在一些实施方式中,所述药学活性成分选自罗哌卡因、布比卡因、左旋布比卡因、美洛昔康、塞来昔布、酮咯酸、曲安奈德中的一种或几种的组合。在一些实施方式中,所述药学活性成分选自酰胺类局麻药与非甾体抗炎药的组合,例如罗哌卡因和美洛昔康组合物、左旋布比卡因和美洛昔康组合物、布比卡因和美洛昔康组合物、罗哌卡因和塞来昔布组合物、左旋布比卡因和塞来昔布组合物、布比卡因和塞来昔布组合物等。
根据本发明的实施方案,所述药学上可接受的释放调节剂选自小分子酯类和表面活性剂。所述小分子酯类为三醋酸甘油酯、硬脂酸异丙酯、月桂酸异丙酯、棕榈酸异丙酯、肉豆蔻酸异丙酯、苯甲酸苄酯。
在一些实施方式中,所述表面活性剂为非离子型表面活性剂。
在一些实施方式中,所述表面活性剂包括硬脂酸聚烃氧40酯、辛酸癸酸聚乙二醇甘油酯、月桂酰聚氧乙烯甘油酯、硬脂酰聚氧乙烯甘油酯、油酰聚氧乙烯甘油酯、维生素E聚乙二醇琥珀酸酯、蛋黄卵磷脂、大豆磷脂、氢化大豆磷脂,泊洛沙姆,聚山梨酯,聚乙二醇-12-羟基硬脂酸酯、丙二醇单辛酸酯等。所述泊洛沙姆可选自例如泊洛沙姆407、泊洛沙姆188,所述聚山梨酯可选自例如聚山梨酯80。
根据本发明的实施方案,所述药学上可接受的酸(f组分)选自醋酸、乳酸、琥珀酸、富马酸、马来酸、甲磺酸、亚油酸、山梨酸、辛酸、壬酸、月桂酸、棕榈酸、油酸、盐酸、邻苯二甲酸、癸酸、肉豆蔻酸、丙酸、丁酸、庚酸、戊酸、苹果酸、酒石酸、草酸、柠檬酸、抗坏血酸、水杨酸、咖啡酸、维生素E琥珀酸等。
根据本发明的实施方案,所述组合物还可以进一步包括一种或多种抗氧化剂。抗氧化剂可用于防止或减少本发明中所述缓释递药系统中磷脂或液体油的氧化。本发明提供的抗氧化剂包括但不限于维生素C(抗坏血酸),半胱氨酸或其盐酸盐,维生素E(生育酚),抗坏血酸棕榈酸酯,谷胱甘肽,α硫辛酸,硫代甘油,丁基羟基茴香醚,二丁基羟基甲苯,乙二胺四乙酸及其钠盐、柠檬酸、酒石酸。
根据本发明的实施方案,所述组合物还可以进一步包括其他药学领域常规的赋形剂,合适的药物赋形剂的实例在Excipients and their use in injectableproducts.PDA J Pharm Sci Technol.第51卷,1997年7-8月,第166-171页和ExcipientSelection In Parenteral Formulation Development,Pharma Times,第45卷,第3期,2013年3月,第65-77页中描述,他们通过引用整体并入本发明中。
根据本发明的实施方案,所述液体油占组合物总量的约20%至约90%(w/w),例如约21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%。在一些实施方案中,所述液体油比例约为30至90%(w/w)。在一些实施方案中,所述液体油比例约为40%至79%(w/w)。
根据本发明的实施方案,所述凝胶因子占组合物总量的2%至50%(w/w),例如2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%。在一些实施方案中,所述凝胶因子占组合物总量2%至30%(w/w)。
根据本发明的实施方案,所述稳定剂占组合物总量的1%至40%(w/w),例如1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%。在一些实施方案中,所述稳定剂占组合物总量5%至30%(w/w)。
根据本发明的实施方案,所述药学活性成分占组合物总量的0.01%至50.0%(w/w)。根据一些实施方案,药学活性成分占组合物总量的0.01%至15%(w/w),例如0.01%、0.05%、0.1%、0.5%、1.0%、1.5%、2.0%、2.5%、3.0%、3.5%、4.0%、4.5%、5.0%、5.5%、6.0%、6.5%、7.0%、7.5%、8.0%、8.5%、9.0%、9.5%、10.0%、10.5%、11.0%、11.5%、12.0%、12.5%、13.0%、13.5%、14.0%、14.5%、15.0%。根据一些实施方式,药学活性成分以3%(w/w)至10%(w/w)的量存在。根据一些实施方式,当药学活性成分选自两种以上时,每种药学活性成分可以占组合物总量的0.01%至10%(w/w),例如0.01%、0.05%、0.1%、0.5%、1.0%、1.5%、2.0%、2.5%、3.0%、3.5%、4.0%、4.5%、5.0%、5.5%、6.0%、6.5%、7.0%、7.5%、8.0%、8.5%、9.0%、9.5%、10.0%。
根据本发明的实施方案,所述溶剂总量占组合物总量的0%至50%(w/w),在一些实施方案中,可以不含有溶剂,在一些实施方案中,所述溶剂总量可以占组合物总量的0.01-50%,优选为2-50%,例如为2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%。在一些实施方案中,所述溶剂总量占组合物总量的5%-50%(w/w),在一些实施方案中,所述溶剂总量占组合物总量的5%-30%(w/w)。当溶剂选自两种以上的组合时,每种溶剂可以占组合物总量的0%至30%(w/w),优选为0.01-30%,例如1.0%、1.5%、2.0%、2.5%、3.0%、3.5%、4.0%、4.5%、5.0%、5.5%、6.0%、6.5%、7.0%、7.5%、8.0%、8.5%、9.0%、9.5%、10.0%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%。
根据本发明的实施方案,所述溶剂为非水溶剂,所述非水溶剂选自醇类、N-甲基吡咯烷酮、苯甲酸苄酯、二甲亚砜中的一种或多种组合。所述醇类选自甲醇、乙醇、正丙醇,异丙醇,正丁醇,异丁醇、叔丁醇、乙二醇、丙二醇、甘油、苯甲醇、苯乙醇、聚乙二醇。
优选的,所述非水溶剂选自苯甲醇、N-甲基吡咯烷酮、二甲亚砜、无水乙醇中的一种或多种组合
根据本发明的实施方案,所述释放调节剂占组合物总量的0%至40%(w/w),优选的,为0.1%至40%(w/w),在一些实施方式中,所述释放调节剂可以占组合物总量的0.1%、0.2%、0.3%、0.4%、0.5%、0.6%、0.7%、0.8%、0.9%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%,在一些实施方式中,当所述释放调节剂选自小分子酯类时,所述释放调节剂用量为1~35%;在一些实施方式中,当所述释放调节剂选自表面活性剂时,所述释放调节剂用量为0.1%至5%(w/w)。
根据本发明实施方案,所述药学上可接受的酸(f组分)占组合物总量的0%至20%(w/w),在一些实施方案中,可以不含酸,在一些实施方案中,所述酸占组合物总量的0.01%至20%,优选为0.05-20%,例如0.05%、0.1%、0.5%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%,在一些实施方式中,所述酸占组合物总量的4%至20%。
本发明提供的药物组合物为半固体制剂。在本发明的药物组合物中,所述药学上可接受的溶剂和释放调节剂可以作为粘度调节剂,使所述组合物适于注射。在一些实施方式中,在30℃时,所述组合物的粘度小于20000cP。在一些实施方式中,在30℃时所述组合物的粘度在5000至10000cP的范围内。在一些实施方式中,在30℃时,所述组合物的粘度在3000至5000cP的范围内。在一些实施方式中,在30℃时,所述组合物的粘度在1000至3000cP的范围内。
本发明提供了一种所述药物组合物的制备方法,包括如下步骤:
(a1)将液体油、药学上可接受的凝胶因子、药学上的稳定剂和溶剂混合,在加热条件下搅拌至澄清均一的混合溶液;
(a2)将至少一种药学上的活性成分添加到所述混合溶液中,搅拌至形成均一混合物;
(a3)将(a2)形成的均一混合物冷却至室温。
根据本发明的实施方案,所述步骤(a1)的混合还包括加入至少一种释放调节剂,例如,所述步骤(a1)可以为将液体油、凝胶因子、药学上的稳定剂、药学上可接受的溶剂与释放调节剂混合。
在一些实施方式中,所述方法包括:
1.在50~70℃下将液体油、凝胶因子、稳定剂、药学上的活性分子和药学上的溶剂混合,直至得到澄清透明溶液。
2.将热溶液过0.22μm滤膜除菌。
3.将所述过滤后的混合溶液冷却至室温。
在一些实施方式中,所述方法包括:
1.在50~70℃下将液体油、凝胶因子、药学上的稳定剂、药学上的活性分子、药学上的溶剂和释放调节剂混合,直至得到澄清透明溶液。
2.将热溶液过0.22μm滤膜除菌。
3.将所述过滤后的混合溶液冷却至室温。
在一些实施方式中,可以根据不同药学活性分子的性质,将较难溶解的活性分子先溶于部分溶剂,再加入由液体油、凝胶因子、剩余部分溶剂加热混合形成的溶液中而制备所需的药物组合物。
在一些实施方式中,所述方法包括:
1.在50~70℃下将液体油、凝胶因子和稳定剂与部分溶剂混合,直至得到澄清透明溶液。
2.将药学上的活性分子加入部分溶剂中,直至完全溶解。
3.将药物溶液与1中的溶液混合均匀。
4.将热溶液过0.22μm滤膜除菌。
5.将所述过滤后的混合溶液冷却至室温。
在一些实施方式中,可以根据不同药学活性分子的性质,将较难溶解的活性分子先溶于部分溶剂,再加入由液体油、凝胶因子、部分溶剂、释放调节剂加热混合形成的溶液中而制备所需的药物组合物。
在一些实施方式中,所述方法包括:
1.在50~70℃下将液体油、凝胶因子,稳定剂,部分溶剂和释放调节剂混合,直至得到澄清透明溶液。
2.将药学上的活性分子加入部分溶剂中,直至完全溶解。
3.将药物溶液与1中的溶液混合均匀。
4.将热溶液过0.22μm滤膜除菌。
5.将所述过滤后的混合溶液冷却至室温。
本发明所述的药物组合物的制备方法,在一些实施方式中,混合溶液自然冷却至室温;在一些实施方式中,混合溶液迅速冷却凝固后于室温放置;在一些实施方式中,混合溶液迅速冷却凝固后于特定温度保温一定时间后于室温放置;在一些实施方式中,混合溶液在体系熔融温度下保温凝固后于室温放置;在一些实施方式中,混合溶液在体系熔融温度下保温凝固后于特定温度保温一定时间后于室温放置。
本发明提供一种包含所述药物组合物的缓释制剂,所述制剂作为储库制剂施用,一方面,所述制剂为可注射的。另一方面,所述制剂可以局部给药。
另一方面,所述制剂可皮下注射,周围神经注射,肌内注射或向伤口直接施用。
另一方面,所述制剂适合在皮肤或粘膜给药。
本发明提供的制剂以单次剂量施用,所含药量可以达到止痛、神经阻滞的效果,可用于防止或减轻局部疼痛。
根据一些实施方式,本发明提供的制剂可在给药部位形成形态稳定的储库,可缓慢持续地释放药物,延长局麻药释放时间,提高治疗效果。
在一些实施方式中,所述制剂施用后可持续有效治疗至少24小时。在一些实施方式中,所述制剂施用后可持续有效治疗至少24至48小时。在一些实施方式中,所述制剂施用后可持续有效治疗至少48至72小时。在一些实施方式中,所述制剂施用后可持续有效治疗至少72小时。根据本发明的实施方案,所述制剂进一步包括填充了所述制剂的包材,所述包材选自以下一种或多种:西林瓶、预灌封注射器、卡式瓶。
术语与缩写
除非另有说明,本申请说明书和权利要求书中记载的基团和术语定义,包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等,可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构,应当属于本申请说明书记载的范围内。
本申请说明书和权利要求书记载的数值范围,当该数值范围被定义或其仅可为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“0~10的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。
当该数值范围被定义为“数”或可以包括“整数”或“非整数”时,应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如,“0~10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数,还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
术语“脂肪烃基”包括饱和或不饱和,直链或具有支链的链状烃基,所述脂肪烃基的类型可选自烷基(饱和脂肪烃基)、烯基、炔基等,所述脂肪烃基的碳原子数优选为1-40,进一步优选为1-30(例如为C1,C2,C3,C4,C5,C6,C6,C7,C8,C9,C10,C11,C12,C13,C14,C15,C16,C17,C18,C19,C20,C21,C22,C23,C24,C25,C26,C27,C28,C29,C30,C31,C32,C33,C34,C35,C36,C37,C38,C30,C40),具体可包括但不限于如下基团:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基,1-丙炔基,2-丙炔基,1-丁炔基,1-甲基-2-丙炔基,3-丁炔基,1-戊炔基和1-己炔基;其他基团中所含“脂肪烃基”部分同上述解释。
术语“烷基”为饱和脂肪烃基,符合上述脂肪烃基中的相关定义,例如所述烷基的碳原子数优选为1-40,进一步优选为1-30,或1-10(例如为C1,C2,C3,C4,C5,C6,C6,C7,C8,C9,C10,C11,C12,C13,C14,C15,C16,C17,C18,C19,C20,C21,C22,C23,C24,C25,C26,C27,C28,C29,C30,C31,C32,C33,C34,C35,C36,C37,C38,C30,C40)。且本领域技术人员可以理解“亚烷基”亦可参照上述脂肪烃基中的相关定义,例如所述亚烷基的碳原子数可以为C1,C2,C3,C4,C5,C6,C6,C7,C8,C9,C10。
术语“生物相容性”是指组合物成分与机体之间的相互作用。
术语“活性成分”是指用于治疗疾病的药物。因此,活性成分、药物可替换使用。此处使用的术语“活性成分”或“药物”包括但不限于局部或全身作用的药物活性物质,其可以通过局部给药或通过注射,如皮下、皮内、肌内及关节内注射进行施用。至少一种活性成分存在于本发明的缓释递药系统中。
术语“油凝胶”是指在液态油中添加凝胶因子而得到的一种热可逆、半固体状且具有一定粘弹性的分散体系。
术语“凝胶因子”是指分子中具有亲脂结构和可相互作用位点,并且具有一定表面活性以及热可逆性的一类物质。
术语“半固体”是指在一定压力下可流动的形态。更具体地,半固体通常在30℃下粘度在100至50000cP之间的粘度,特别是在30℃下100至20000cP的之间粘度。
术语“小分子酯类”是指分子量小于500的酯类,室温下为液体。
本发明所用的术语“酰胺型”是指酰胺或卡因类局部麻醉剂,如布比卡因,左旋布比卡因,罗哌卡因,甲哌卡因,利多卡因等。酰胺类局麻药一般由亲脂部分和亲水部分组成,亲脂性部分,可为芳烃或芳杂环,而以苯环作用最强。苯环上引入给电子基团例如氨基等可使活性增强。亲水部分一般为仲胺、叔胺或吡咯烷、哌啶、吗啉等,以叔胺最为常见。pKa一般在7.5~7.9之间,生理条件下为离子型。
本发明使用的缩写词具有如下定义:SPC为大豆磷脂酰胆碱(大豆磷脂),EPC为蛋黄磷脂酰胆碱(蛋黄磷脂),HSPC为氢化大豆磷脂酰胆碱,DLPC为二月桂酰磷脂酰胆碱,DMPC为二肉豆蔻酰基磷脂酰胆碱,DPPC为二棕榈酰基磷脂酰胆碱,DSPC为二硬脂酰基磷脂酰胆碱,DEPC为二芥酰基卵磷脂,DOPC为二油酸酰基磷脂酰胆碱(二油酸酰基卵磷脂),POPC为棕榈酰基油酰基卵磷脂,DEPC为二芥酰基卵磷脂,DOPC为二油酸酰基卵磷脂,POPC为棕榈酰基油酰基卵磷脂,DSPA为二硬脂酰磷脂酸,DOPE为二油酰磷脂酰乙醇胺,DPPA为二棕榈酰磷脂酸,M-lysoPC为肉豆蔻酰溶血磷脂,P-lysoPC为棕榈酰溶血磷脂,S-lysoPC为1-硬脂酰-溶血磷脂酰胆碱,DPPE为二棕榈酰磷脂酰乙醇胺,DSPE为二硬脂酰磷脂酰乙醇胺,DOPG为二油酰磷脂酰甘油,DMPE为二肉豆蔻酰磷脂酰乙醇胺,DMPG为二肉豆蔻酰磷脂酰甘油,DPPG为二棕榈酰磷脂酰甘油,POPG为1-棕榈酰-2-油酰磷脂酰甘油,DSPG为二硬脂酰酰磷脂酰甘油,DPPS为二棕榈酰磷酯酰丝氨酸,PI为磷脂酰肌醇,BA为苯甲醇,NMP为N-甲基吡咯烷酮,DMSO为二甲基亚砜,BHA代表丁基羟基茴香醚,BHT代表二丁基羟基甲苯,BUP为布比卡因,ROP为罗哌卡因,MLX为美洛昔康,CHO代表胆固醇,PRX为吡罗昔康,LBUP为左旋布比卡因,TAC为曲安奈德,KTL为酮咯酸,VE代表维生素E,VES代表维生素E琥珀酸。
有益效果
1)本发明提供了一种缓释制剂组合物,该组合物制剂在常温下呈现半固体,在给药部位可直接作为药物储库。本发明所选用的凝胶因子,与制剂其他成分具有良好的生物相容性,可使液体油固化,满足药物缓释释放需求。
2)本发明还惊奇地发现,在制剂体系中加入合适的稳定剂,可以改善组合物在长期放置过程中出现的变色问题,提高组合物的持油性,增强组合物的凝胶特性,降低组合物粘度等;
3)本发明的缓释递药液体组合物具有合适的粘度,易于给药;本发明的缓释递药半固体组合物可直接施用于给药部位,便于临床给药。
4)本发明组合物刺激性小,具有良好的用药安全性及耐受性。
5)本发明提供的缓释制剂系统,能够使得活性药物成分实现良好的释放性能,降低突释的可能性。
6)本发明的组合物尤其适用于具有麻醉、镇痛活性的药物制剂开发,相对于其他缓释镇痛药体系具有更多的优势,例如对于镇痛活性成分的释放持续稳定,不仅可以注射给药,而且适用于稳定便捷的局部给药,患者耐受性好,副作用少。
附图说明
图1-1和图1-2是组合物1010在2-8℃和25℃的流变学结果
图1-3和图1-4是组合物1013在2-8℃和25℃的流变学结果
图1-5~1-7是组合物1051和1052、1030、1031的流变学结果
图1-8是组合物1010和1013的粘度-温度变化图谱
图1-9是组合物1051和1052的粘度-温度变化图谱
图1-10是组合物1053和1054的粘度-转速变化图谱
图2-1和2-2是组合物1047的布比卡因和美洛昔康血药浓度时间曲线。
图2-3和2-4是组合物1048的布比卡因和美洛昔康血药浓度时间曲线。
图3-1是组合物1076、1077和1078对大鼠CFA炎症痛模型的机械痛觉敏感的影响。Pre表示造模前基础机械痛阈值,黑色实心点表示与模型组相比,结果具有统计学差异(p<0.05)。
图4-1和4-2是组合物1079的罗哌卡因和美洛昔康血药浓度时间曲线。
图5-1和5-2是组合物1080的罗哌卡因和美洛昔康血药浓度时间曲线。
图5-3和5-4是组合物1081的罗哌卡因和美洛昔康血药浓度时间曲线。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实验材料:
蓖麻油:CO;
混合脂肪酸甘油酯(硬脂):硬脂36型,硬脂38型,SUPPOCIRE AM,SUPPOCIRE CM,GELUCIRE 43/01,SOFTISAN 378。
双硬脂酸甘油酯:Precirol ATO5
山嵛酸甘油酯:COMPRITOL 888ATO
磷脂:SPC,HSPC、DMPC、DPPC、DSPC、DEPC、EPC、DOPC
实施例1
稳定剂对组合物外观的影响
按照表1-1至表1-3中所示配制含有不同凝胶因子的组合物,并于室温长期放置20个月,将组合物与标准比色液Y(黄色)1~10号对比,考察组合物外观颜色的变化。
表1-1单硬脂酸甘油酯作为凝胶因子的组合物长期放置后的外观颜色
表1-2硬脂作为凝胶因子的组合物长期放置后的外观颜色
表1-3山嵛酸甘油酯作为凝胶因子的组合物长期放置后的外观颜色
本发明意外发现只含有脂肪酸甘油酯作为凝胶因子的油凝胶制剂在长期留样过程中颜色均发生不同程度变深,加入稳定剂(例如SPC、HSPC)的组合物长期放置20个月,外观色号在Y7~8号之间,颜色变化明显小于其他油凝胶组合物,能够明显提高油凝胶组合物的外观稳定性。
实施例2
组合物的持油性研究
按照下表2-1~2-9中所示的每种成分制备含有不同比例凝胶因子的药物组合物。称取0.5g药物组合物,置于离心管中,以不同转速离心,离心后将离心管倒置,观察组合物析油情况。
表2-1不含稳定剂的油凝胶组合物持油性研究
表2-2加入稳定剂后油凝胶组合物的持油性对比
表2-3稳定剂用量对油凝胶组合物的持油性研究
表2-4稳定剂用量对油凝胶组合物的持油性研究
表2-5稳定剂用量对油凝胶组合物的持油性研究
表2-6含有稳定剂油凝胶组合物的持油性研究
表2-7含有稳定剂油凝胶组合物的持油性研究
表2-8含有稳定剂的油凝胶组合物的持油性研究
表2-9含有稳定剂的油凝胶组合物的持油性研究
持油性是评价油凝胶结构稳定性的指标之一,为了保证凝胶因子对液体油的固化能力,防止在长期放置过程中液体油析出的现象,需对制剂的持油性进行研究,考察油凝胶中最大载油能力。本发明意外的发现含有稳定剂的组合物能显著提高持油性,提高物理稳定性,有效降低储存期间析油风险。
实施例3
油凝胶组合物的粘度测量
按表3-1至3-3制备含有不同稳定剂和有机溶剂用量的药物组合物。在70℃下将表中原辅料混合,边加热边搅拌直至形成透明均一的溶液,冷却至室温形成固态凝胶状物质。随后使用配备14号转子的粘度计通过轴方法测量药物组合物的粘度,检测温度为30℃转速为10rpm,粘度检测结果见下表3-1至3-3。
表3-1不含稳定剂的药物组合物的粘度结果
表3-2含有不同稳定剂的药物组合物的粘度结果
3-3含有不同有机溶剂用量的药物组合物的粘度结果
本发明意外的发现加入稳定剂后(如SPC、DEPC、CHO、DOPC等),能够显著降低药物组合物的粘度,同时有机溶剂的用量也影响整个体系的粘度。因此可以通过调整稳定剂和有机溶剂的比例,对药物组合物的粘度进行优化,使其更易于临床给药。
实施例4
通针性考察
按照表4-1至4-4配制含有不同有机溶剂和不同稳定剂的油凝胶组合物,对表中组合物进行通针性检测,考察最大推力。检测结果见下表4-1至4-4。
表4-1通针性考察
表4-2不同有机溶剂用量的通针性考察
表4-3不同稳定剂的通针性考察
表4-4含有不同稳定剂用量的药物组合物的通针性结果
通常为了医生给药方便,临床给药通针性要求最大推力不大于2kg。
本发明考察了有机溶剂用量对通针性的影响,结果表明提高有机溶剂用量,可以降低推力,更有利于临床给药。同时,在油凝胶组合物中加入其他稳定剂均可以达到降低推力的作用。
实施例5
组合物的流变学研究
按表5-1至5-4制备油凝胶组合物,进行流变学研究。流变仪型号:TA DHR-1样品量:1mL。测定模式:振荡模式:时间扫描,固定Strain 0.5%,频率1Hz;振荡模式:频率扫描,固定Strain 0.5%,频率扫描范围为0.1-100rad/s;流动模式:粘度扫描,剪切速率范围为0.01-100 1/s;流动模式:粘度变温扫描,温度变化范围20℃-60℃,固定剪切速率0.11/s
表5-1组合物成分
表5-2组合物成分
表5-3组合物成分
表5-4组合物成分
流变学中的储能模量G′和损耗模量G”参数可用于评价凝胶特性。理论上甘油酯的储能模量G′越大,凝胶强度越强,凝胶网络结构越稳定。当储能模量(G′)大于损耗模量(G”)时,样品呈现凝胶特性。图1-1至1-7分别为表5-1~5-3油凝胶组合物的流变性质结果。本发明意外发现含有SPC的组合物(1013)G′大于G”,具有明显的凝胶特性,而不含有SPC的组合物(1010、1030、1031)未表现出凝胶性质。同时增加稳定剂的用量(1051和1052),可增强制剂的凝胶强度。
图1-8和图1-9为组合物1010、1013、1051和1052粘度随温度变化的趋势,根据变化趋势可推断组合物的胶凝温度,结果见表5-5,由表5-5可知,加入SPC后能降低组合物的胶凝温度,更有利于放大生产及灌装。
表5-5组合物胶凝温度
编号 | 胶凝温度(℃) |
1010 | 49.1 |
1013 | 45.2 |
1051 | 40.2 |
1052 | 40.2 |
图1-10为组合物1053和1054粘度随转速变化的趋势,根据变化趋势可以看出本发明的油凝胶组合物存在剪切稀化的性质,更有利于临床给药。同时稳定剂SPC的用量增加,组合物粘度有一定程度的降低。
实施例6
凝固温度研究
按表6-1至6-3制备油凝胶组合物,在显微镜下观察组合物溶解后冷却时的凝固温度,考察有机溶剂和稳定剂对凝固温度的影响。检测结果见下表6-1至6-3。
表6-1不含稳定剂的组合物的凝固温度
表6-2含有不同有机溶剂的组合物的凝固温度
表6-3含有不同稳定剂的组合物的凝固温度
本发明意外发现加入有机溶剂和稳定剂可以降低组合物的凝固温度,更有利于生产灌装。
实施例7
不同活性成分的油凝胶组合物
按照下表7-1中所示的每种成分制备含有不同主要活性成分的油凝胶组合物。在70℃下将表中原辅料混合,边加热边搅拌直至形成透明均一的溶液,冷却至室温均可形成固态凝胶状物质。
表7-1不同活性成分的组合物
表7-2不同活性成分组合物
实施例8
含有不同浓度的药物组合物
按照下表8-1中所示的每种成分制备含有不同主要活性成分的油凝胶组合物。在70℃下将表中原辅料混合,边加热边搅拌直至形成透明均一的溶液,冷却至室温均可形成固态凝胶状物质。
表8-1含有不同抗氧化剂的药物组合物
实施例9
油凝胶组合物的体内施用。
犬体内药代动力学研究如下。重量约10kg的比格犬实验前禁食12小时(取下喂食的食盒)以上,自由饮水,给药后4小时给食。各组按皮下注射6mg/kg进行给药,样品信息见表9-1。各组动物于给药前取0小时、于给药后0.5、1、2、3、6、8、12、24、36、48、60、72和96小时各采集血样约0.5mL至EDTA-2K+抗凝的采血管中,全血经8000rpm离心5min后收集血浆,随后通过LC-MS/MS检测血浆样品中的药物浓度。
表9-1组合物处方信息
组合物给药后96小时内的BUP和MLX的血药浓度-时间曲线见图2-1至2-4。
实施例10
油凝胶组合物的体内施用
大鼠药效研究如下。大鼠于实验前三天每天测定一次PWT值,并于第四天造模前测定一次PWT为造模前基础值,随即所有大鼠的右后爪分别给予100μL CFA,炎症造模后24h再测定一次PWT值即为造模后基础值,经足底皮下注射给予组合物,样品信息见表10-1,模型组不做给药处理,在给药后不同时间点用Von Frey单丝刺激大鼠后肢足底中部,测试其机械性缩爪阈值(paw withdrawal threshold,PWT)作为疼痛阈值。检测时间分别为给药后30min、1h、4h、8h、12h、24h、48h、72h、92h。
表10-1样品信息
结果如图3-1所示,造模前,各组大鼠的机械痛阈值(PWT)均保持在21-24g左右;造模后24h,机械痛阈值(PWT)下降到4-6g,可见CFA造模后大鼠的机械性痛觉过敏十分明显。组合物1076在给药后30min即显著提高了大鼠的PWT值(p<0.05),并且效应可持续到96h,差异具有统计学意义(p<0.05)。组合物1078在给药后4h出现镇痛效应(p<0.05),持续到12h后镇痛效应消失(p>0.05),说明其效应维持时间在12h到24h之间。组合物1077直到8h才出现镇痛效应(p<0.05),并维持到12h,之后镇痛效果出现波动,在48h处再次显示出镇痛效应(p<0.05)。
实施例11
油凝胶组合物的体内施用。
犬体内药代动力学研究如下。重量约10kg的比格犬实验前禁食12小时(取下喂食的食盒)以上,自由饮水,给药后4小时给食。各组按皮下注射6mg/kg进行给药,样品信息见表11-1。各组动物于给药前取0小时、于给药后0.5、1、2、3、6、8、12、24、36、48、60、72和96小时各采集血样约0.5mL至EDTA-2K+抗凝的采血管中,全血经8000rpm离心5min后收集血浆,随后通过LC-MS/MS检测血浆样品中的药物浓度。
表11-1组合物处方信息
组合物给药后96小时内的ROP和MLX的血药浓度-时间曲线见图4-1至4-2。
实施例12
油凝胶组合物的体内施用。
犬体内药代动力学研究如下。重量约10kg的比格犬实验前禁食12小时(取下喂食的食盒)以上,自由饮水,给药后4小时给食。各组按皮下注射6mg/kg进行给药,样品信息见表12-1。各组动物于给药前取0小时、于给药后0.5、1、2、3、6、8、12、24、36、48、60、72和96小时各采集血样约0.5mL至EDTA-2K+抗凝的采血管中,全血经8000rpm离心5min后收集血浆,随后通过LC-MS/MS检测血浆样品中的药物浓度。
表12-1组合物处方信息
组合物给药后96小时内的ROP和MLX的血药浓度-时间曲线见图5-1至5-4。
以上,对本发明示例性的实施方式进行了说明。但是,本发明的保护范围不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (11)
2.根据权利要求1的药物组合物,其特征在于,所述式I中,每个Ra独立地选自烷基,优选的,每个Ra独立地选自C1-40烷基,更优选的,每个Ra独立地选自C7-40烷基;
优选的,R’、R”选自H,R”’选自(C11-40烷基)C(=O);或R’选自H,R”选自RaCO,且R”、R”’中各自独立所选Ra烷基的碳数总和大于18;或R’、R”、R”’均选自RaCO,且R’、R”、R”’中各自独立所选Ra烷基的碳数总和大于17;
优选的,所述式II中,每个R1、R2相同或不同,彼此独立地选自C10-30饱和或不饱和脂肪烃基,例如C13-21烷基;每个R3、R4、R5相同或不同,彼此独立地选自H或C1-10烷基,例如彼此独立地选自H,甲基,乙基;所述L选自C1-10亚烷基,优选的,L选自C1-6亚烷基,例如为亚甲基,亚乙基;式III所示化合物中,R选自C1-10烷基,例如C8-10烷基。
3.根据权利要求1或2的药物组合物,其特征在于,
所述b组分药学上可接受的凝胶因子包括例如单硬脂酸甘油酯,双硬脂酸甘油酯、三硬脂酸甘油酯、单山嵛酸甘油酯、双山嵛酸甘油酯、单棕榈酸硬脂酸甘油酯、双棕榈酸硬脂酸甘油酯、单棕榈酸甘油酯、双棕榈酸甘油酯、棕榈酸硬脂酸甘油酯中的一种或多种;
所述c组分药学上可接受的稳定剂选自HSPC(氢化大豆磷脂)、DMPC(二肉豆蔻酰基磷脂酰胆碱)、DPPC(二棕榈酰基磷脂酰胆碱)、DSPC(二硬脂酰基磷脂酰胆碱)、DLPC(二月桂酰磷脂酰胆碱)、SPC大豆磷脂酰胆碱(大豆磷脂),EPC(蛋黄磷脂),油菜籽磷脂,向日葵磷脂,DEPC(二芥酰基卵磷脂),DOPC(二油酸酰基卵磷脂),POPC(棕榈酰基油酰基卵磷脂)、鞘磷脂、二硬脂酰磷脂酸(DSPA)、二油酰磷脂酰乙醇胺(DOPE)、二棕榈酰磷脂酸(DPPA)、肉豆蔻酰溶血磷脂(M-lysoPC)、棕榈酰溶血磷脂(P-lysoPC)、1-硬脂酰-溶血磷脂酰胆碱(S-lysoPC)、二棕榈酰磷脂酰乙醇胺(DPPE)、二硬脂酰磷脂酰乙醇胺(DSPE)、二油酰磷脂酰甘油(DOPG)、二肉豆蔻酰磷脂酰乙醇胺(DMPE)、二肉豆蔻酰磷脂酰甘油(DMPG)、二棕榈酰磷脂酰甘油(DPPG)、1-棕榈酰-2-油酰磷脂酰甘油(POPG)、二硬脂酰酰磷脂酰甘油(DSPG)、二棕榈酰磷酯酰丝氨酸(DPPS)、磷脂酰肌醇(PI)、胆固醇(CHO)中的一种或多种。
4.根据权利要求1-3任一项所述的药物组合物,其特征在于,所述药物组合物还包含e.至少一种药学上可接受的溶剂;
和/或所述药物组合物可以进一步包含g.药学上可接受的释放调节剂;
和/或所述药物组合物可以进一步包含f.药学上可接受的酸。
5.根据权利要求1-3任一项所述的药物组合物,其特征在于,所述液体油选自蓖麻油、芝麻油、玉米油、大豆油、橄榄油、红花油、棉籽油、花生油、鱼油、茶油、杏仁油、巴巴苏油、黑醋栗种子油、琉璃苣油、卡诺拉油、棕榈油、棕榈仁油、向日葵油、中链甘油三酯、二油酸甘油酯、单油酸甘油酯中的一种或多种组合。
6.根据权利要求1-4任一项所述的药物组合物,其特征在于,所述至少一种药学活性成分不限于治疗类型,并可为抗炎药、局麻药、镇痛药、抗精神失常药、抗焦虑药、镇静催眠药、抗抑郁药、抗高血压药、类固醇激素、抗癫痫药、杀菌剂、抗惊厥药、抗帕金森病药、中枢神经兴奋药、抗精神病药、抗心律失常药、抗心绞痛药、抗甲状腺药、解毒药、止吐药、降糖药、抗结核病药、抗艾滋病药、抗乙肝药、抗肿瘤药、抗排斥药及其混合物。
7.根据权利要求4所述的药物组合物,其特征在于,所述药学上可接受的释放调节剂选自小分子酯类和表面活性剂;所述小分子酯类为三醋酸甘油酯、硬脂酸异丙酯、月桂酸异丙酯、棕榈酸异丙酯、肉豆蔻酸异丙酯、苯甲酸苄酯;所述药学上可接受的酸选自醋酸、乳酸、琥珀酸、富马酸、马来酸、甲磺酸、亚油酸、山梨酸、辛酸、壬酸、月桂酸、棕榈酸、油酸、盐酸、邻苯二甲酸、癸酸、肉豆蔻酸、丙酸、丁酸、庚酸、戊酸、苹果酸、酒石酸、草酸、柠檬酸、抗坏血酸、水杨酸、咖啡酸、维生素E琥珀酸。
8.根据权利要求1-6任一项所述的药物组合物,其特征在于,所述液体油占组合物总量的约20%至约90%(w/w);所述凝胶因子占组合物总量的2%至50%(w/w);所述稳定剂占组合物总量的1%至40%(w/w);所述药学活性成分占组合物总量的0.01%至50.0%(w/w);所述溶剂总量占组合物总量的0%至50%(w/w)。
9.根据权利要求1-7任一项所述的药物组合物的制备方法,其特征在于,包括如下步骤:
(a1)将液体油、药学上可接受的凝胶因子、药学上的稳定剂和溶剂混合,在加热条件下搅拌至澄清均一的混合溶液;
(a2)将至少一种药学上的活性成分添加到所述混合溶液中,搅拌至形成均一混合物;
(a3)将(a2)形成的均一混合物冷却至室温;
根据本发明的实施方案,所述步骤(a1)的混合还包括加入至少一种释放调节剂,例如,所述步骤(a1)可以为将液体油、凝胶因子、药学上的稳定剂、药学上可接受的溶剂与释放调节剂混合。
10.一种包含权利要求1-7任一项所述的药物组合物的缓释制剂,其特征在于,所述制剂作为储库制剂施用,优选的,所述制剂为可注射的或所述制剂可以局部给药。
11.根据权利要求9所述的制剂,其特征在于,所述制剂进一步包括填充了所述制剂的包材,所述包材选自以下一种或多种:西林瓶、预灌封注射器、卡式瓶。
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202410345219.9A CN118304253A (zh) | 2021-01-14 | 2021-01-14 | 一种缓释制剂组合物 |
CN202110051096.4A CN114762676B (zh) | 2021-01-14 | 2021-01-14 | 一种缓释制剂组合物 |
CA3196937A CA3196937A1 (en) | 2021-01-14 | 2022-01-14 | Sustained-release preparation composition |
KR1020237017771A KR20230096056A (ko) | 2021-01-14 | 2022-01-14 | 서방성 제제 조성물 |
PCT/CN2022/071928 WO2022152232A1 (zh) | 2021-01-14 | 2022-01-14 | 一种缓释制剂组合物 |
US18/253,429 US20230398089A1 (en) | 2021-01-14 | 2022-01-14 | Sustained-release formulation composition |
EP22739108.3A EP4279065A1 (en) | 2021-01-14 | 2022-01-14 | Sustained-release preparation composition |
JP2023526286A JP2023547222A (ja) | 2021-01-14 | 2022-01-14 | 徐放性製剤組成物 |
AU2022208128A AU2022208128A1 (en) | 2021-01-14 | 2022-01-14 | Sustained-release preparation composition |
TW111101767A TW202228645A (zh) | 2021-01-14 | 2022-01-14 | 緩釋製劑組合物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110051096.4A CN114762676B (zh) | 2021-01-14 | 2021-01-14 | 一种缓释制剂组合物 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410345219.9A Division CN118304253A (zh) | 2021-01-14 | 2021-01-14 | 一种缓释制剂组合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114762676A true CN114762676A (zh) | 2022-07-19 |
CN114762676B CN114762676B (zh) | 2024-03-08 |
Family
ID=82363038
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410345219.9A Pending CN118304253A (zh) | 2021-01-14 | 2021-01-14 | 一种缓释制剂组合物 |
CN202110051096.4A Active CN114762676B (zh) | 2021-01-14 | 2021-01-14 | 一种缓释制剂组合物 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202410345219.9A Pending CN118304253A (zh) | 2021-01-14 | 2021-01-14 | 一种缓释制剂组合物 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20230398089A1 (zh) |
EP (1) | EP4279065A1 (zh) |
JP (1) | JP2023547222A (zh) |
KR (1) | KR20230096056A (zh) |
CN (2) | CN118304253A (zh) |
AU (1) | AU2022208128A1 (zh) |
CA (1) | CA3196937A1 (zh) |
TW (1) | TW202228645A (zh) |
WO (1) | WO2022152232A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116041342A (zh) * | 2022-12-30 | 2023-05-02 | 加立(深圳)生物科技有限公司 | 罗哌卡因/美洛昔康盐的一水合物i晶型、药物组合物及其制备方法和应用 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11992483B2 (en) | 2021-03-31 | 2024-05-28 | Cali Biosciences Us, Llc | Emulsions for local anesthetics |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5976530A (ja) * | 1982-10-26 | 1984-05-01 | Mitsuo Matsumoto | 油性ゲルの製造方法 |
WO2019108602A1 (en) * | 2017-11-28 | 2019-06-06 | University Of Florida Research Foundation | Methods and compositions for retinal drug delivery |
US20200179406A1 (en) * | 2017-12-06 | 2020-06-11 | Mira Pharma Corporation | Injectable long-acting semi-solid gel formulations |
CN111655236A (zh) * | 2017-12-06 | 2020-09-11 | 湖州惠中济世生物科技有限公司 | 可注射长效局麻药半固体凝胶制剂 |
CN113018248A (zh) * | 2019-12-23 | 2021-06-25 | 南京清普生物科技有限公司 | 一种缓释递药系统 |
CN113827547A (zh) * | 2020-06-23 | 2021-12-24 | 南京清普生物科技有限公司 | 一种缓释制剂组合物 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL2767292T3 (pl) | 2004-09-17 | 2017-08-31 | Durect Corporation | Miejscowa kompozycja znieczulająca o przedłużonym uwalnianiu zawierająca SAIB |
CN108743952B (zh) * | 2018-06-11 | 2021-08-31 | 西安力邦医药科技有限责任公司 | 局部麻醉药的磷脂-混溶剂-油缓释递药系统组方与制备方法 |
CN109316602A (zh) * | 2018-11-13 | 2019-02-12 | 西安力邦医药科技有限责任公司 | 一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用 |
-
2021
- 2021-01-14 CN CN202410345219.9A patent/CN118304253A/zh active Pending
- 2021-01-14 CN CN202110051096.4A patent/CN114762676B/zh active Active
-
2022
- 2022-01-14 US US18/253,429 patent/US20230398089A1/en active Pending
- 2022-01-14 WO PCT/CN2022/071928 patent/WO2022152232A1/zh active Application Filing
- 2022-01-14 TW TW111101767A patent/TW202228645A/zh unknown
- 2022-01-14 CA CA3196937A patent/CA3196937A1/en active Pending
- 2022-01-14 JP JP2023526286A patent/JP2023547222A/ja active Pending
- 2022-01-14 KR KR1020237017771A patent/KR20230096056A/ko unknown
- 2022-01-14 AU AU2022208128A patent/AU2022208128A1/en active Pending
- 2022-01-14 EP EP22739108.3A patent/EP4279065A1/en active Pending
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5976530A (ja) * | 1982-10-26 | 1984-05-01 | Mitsuo Matsumoto | 油性ゲルの製造方法 |
WO2019108602A1 (en) * | 2017-11-28 | 2019-06-06 | University Of Florida Research Foundation | Methods and compositions for retinal drug delivery |
US20200179406A1 (en) * | 2017-12-06 | 2020-06-11 | Mira Pharma Corporation | Injectable long-acting semi-solid gel formulations |
CN111655236A (zh) * | 2017-12-06 | 2020-09-11 | 湖州惠中济世生物科技有限公司 | 可注射长效局麻药半固体凝胶制剂 |
CN113018248A (zh) * | 2019-12-23 | 2021-06-25 | 南京清普生物科技有限公司 | 一种缓释递药系统 |
CN113827547A (zh) * | 2020-06-23 | 2021-12-24 | 南京清普生物科技有限公司 | 一种缓释制剂组合物 |
Non-Patent Citations (1)
Title |
---|
张春燕;孙考祥;: "溶剂交换型原位成型植入剂的研究进展", 中国新药杂志, no. 21 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116041342A (zh) * | 2022-12-30 | 2023-05-02 | 加立(深圳)生物科技有限公司 | 罗哌卡因/美洛昔康盐的一水合物i晶型、药物组合物及其制备方法和应用 |
CN116041342B (zh) * | 2022-12-30 | 2024-02-20 | 加立(深圳)生物科技有限公司 | 罗哌卡因/美洛昔康盐的一水合物i晶型、药物组合物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
TW202228645A (zh) | 2022-08-01 |
US20230398089A1 (en) | 2023-12-14 |
WO2022152232A1 (zh) | 2022-07-21 |
KR20230096056A (ko) | 2023-06-29 |
JP2023547222A (ja) | 2023-11-09 |
CN118304253A (zh) | 2024-07-09 |
CA3196937A1 (en) | 2022-07-21 |
AU2022208128A1 (en) | 2023-07-06 |
CN114762676B (zh) | 2024-03-08 |
EP4279065A1 (en) | 2023-11-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113018248B (zh) | 一种缓释递药系统 | |
US10912772B2 (en) | Opioid formulations | |
US20130190341A1 (en) | High bioavailability opioid formulations | |
US20230398089A1 (en) | Sustained-release formulation composition | |
CN113827547A (zh) | 一种缓释制剂组合物 | |
KR20180085716A (ko) | 방출 조절 제제 | |
US20240226091A9 (en) | Opioid formulations | |
CN113941002B (zh) | 一种小分子药物缓释递药系统 | |
CN113941004B (zh) | 一种高浓度局麻药的缓释组合物 | |
WO2023115311A1 (zh) | 一种缓释制剂组合物 | |
TW202325295A (zh) | 緩釋製劑組合物 | |
WO2021143746A1 (zh) | 一种非水缓释递药系统 | |
EP3630191A2 (en) | High-concentration fulvestrant compositions | |
JPH06321771A (ja) | 経皮投与用基剤 | |
BR122020002774B1 (pt) | Líquido e cápsula resistentes ao abuso parenteral | |
BR122020002781B1 (pt) | Líquido e cápsula resistentes ao abuso parenteral | |
BR112015022583B1 (pt) | Líquido e cápsula resistente ao abuso parenteral |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40068519 Country of ref document: HK |
|
GR01 | Patent grant | ||
GR01 | Patent grant |